Cryptococcus neoformans is an opportunistic fungus and an important cause of central nervous system infections among immunocompromised individuals, especially in HIV-reactive and organ transplant recipients. Cryptococcal meningitis presenting as the initial manifestation of diabetes is rare in published literature. We present a case of C. neoformans meningitis in a patient with newly diagnosed Type II diabetes mellitus.

Cryptococcus neoformans is an ubiquitous encapsulated yeast, an important fungal pathogen causing CNS infection in HIV positive and organ transplant recipient individual. The infection occurs following inhalation through the respiratory pathway. The organism then disseminates via blood and has a propensity to localize to the central nervous system, causing meningitis/meningoencephalitis. Individuals with uncontrolled diabetics are prone to infections due to numerous factors as the glucose-rich blood serves as an excellent media for growth. Cryptococcal neoformans meningitis presenting initially as the sole manifestation of diabetes is rare. We report a fatal case of Cryptococcal meningitis in a de novo detected diabetic patient.

Case Report

A 60-year-old male was admitted for unremitting, severe, right frontal headache associated with vomiting of 1-month duration. He had altered mental status with intractable hiccough, increased urinary frequency, generalized weakness, gait ataxia, and slurred speech in the preceding 7 days. His past medical history was unremarkable. He retired as an agriculturist 5 years before presentation. The patient's spouse denied recent travel or exposure to pets.

The present case was a newly detected Type II diabetic individual in diabetic ketoacidotic state with low CD4 count. Based on the above findings, a diagnosis of C. neoformans meningitis with secondary bacteremia was considered.

He was started on intravenous liposomal amphotericin B, standard dose (2–3 mg/kg/day) as induction phase along with parenteral imipenem for 2 weeks. Flucytosine was not available. Over the next 2 weeks, he significantly improved. Repeat CSF culture after 2 weeks of antifungal therapy was negative for C. neoformans. He was then advised to continue maintenance therapy with oral fluconazole of 400 mg/day for next 8 weeks. At discharge, he was alert, ambulant, and afebrile, with minimal bilateral abduction paresis of eyes. He was lost to follow-up. Subsequent telephone conversation with his son revealed that he had expired on day 40th after discharge from hospital. He had symptoms of respiratory distress a day prior.

Discussion

C. neoformans meningitis is relatively uncommon among non-HIV-infected person. Kiertiburanakul et al. showed that conditions associated with Cryptococcal infection in non-HIV individual included immunosuppressive drug treatment (41%), systemic lupus erythematous (16%), malignancies (16%), and diabetes mellitus (14%).[1] Although relatively uncommon, our case has shown diabetes mellitus remains an important cause for C. neoformans meningitis. To the best of our knowledge, the present case is the first report of C. neoformans meningitis, as the initial manifestation of Type II diabetes mellitus and patient had severe immunosuppression at presentation

In diabetic patients, persistent hyperglycemic environment favors immune dysfunction, leading to dysfunction of neutrophil activity (chemotaxis and phagocytosis), reduced T lymphocyte response and humoral immunity, and depression of antioxidant system.[2] Fungal infection in diabetes mainly occurs due to neutrophil dysfunction. Studies have revealed that a deficiency of the complement C4 component in diabetes mellitus is associated with polymorphonuclear dysfunction and reduced cytokine response.[3],[4]

C. neoformans is the most common cause of fungal meningitis in HIV and non-HIV individuals.[5] It is thought to be acquired through inhaling soil contaminated with bird droppings. Two species, transmitted by inhalation, are the principal human pathogens: C. neoformans and Cryptococcus gattii.[6]C. neoformans causes cryptococcal meningitis in immunocompromised patients, whereas C. gattii is associated with illness in immunocompetent individuals.[7] Initially, we thought that C. gattii was the responsible species as our patient was neither HIV-infected nor an organ transplant recipient, and there was no history of malignancy or use of immunosuppressant drugs. However, his CD4+ count showed that he could be immunocompromised. Studies have demonstrated lymphocyte dysfunction and proliferative function of CD4 T lymphocytes and their response to antigens are impaired when the HbA1c is ≥8%.[8] In the present case, HbA1c was higher that might have caused lymphocyte dysfunction and impaired proliferation of CD4 lymphocyte and finally low CD4 count.

The most common manifestations of central nervous system (CNS) cryptococcosis are meningitis and menigoencephalitis and are usually subacute or chronic in nature. Headache and confusion is the most common feature; classical meningism occurs in <20% of patients.[9] Cranial nerve palsies and seizure occur with raised intracranial pressure. Neurological infection may be complicated by mass lesions (cryptococcomas) that occur more commonly with C. gattii than C. neoformans. The present case had asymmetrical menigoencephalitis with predominant involvement of right parietal and occipital lobe.

Our patient had de novo detected diabetic state and he was in diabetic ketoacidotic state during presentation with CNS cryptococcal infection and secondary bacterial sepsis. Although he recovered initially and repeat CSF culture at 2 weeks was negative, still he succumbed with symptoms suggestive of respiratory tract infection. Probably, the cause may be respiratory cryptococcosis or secondary bacterial infection. IDSA 2010 guidelines recommended 2 weeks of combination of amphotericin (0.7–1 mg/kg/day) and flucytosine (100 mg/kg/day) for most cases of cryptococcal meningitis but also suggested at least 4–6 weeks of same combination for induction therapy in non-HIV infected, nontransplant hosts and at least 6 weeks for those with cerebral cryptococcomas.[10] Hence, in the present case ideally, he should have received at least 4 weeks amphotericin even if CSF cultures were negative. Second, since flucytosine was unavailable, the combination of amphotericin B with fluconazole is recommended during induction phase as per guidelines.

Conclusion

Cryptococcal meningitis should be considered in the differential diagnosis for all individuals, including non-HIV patients, presenting with chronic headache, altered sensorium in the presence of fever. Non-HIV, nontransplant recipient requires a longer duration of combination therapy than HIV-infected individuals. Diabetic patients are at increased risk of opportunistic infection similar to HIV patients. Strict hyperglycemic control and longer parenteral antifungal should be a goal to prevent mortality.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.